PROJECT SUMMARY Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the US and worldwide. Studies provide strong evidence that long-term exposures to many air pollutants (e.g. particulate matter < 2.5 microns in diameter (PM2.5), ozone, nitrogen dioxide (NO2) and weather variables (e.g. summer temperature variability, heat and cold waves) are associated with CVD. However most of these studies estimate the impact of long-term exposure to only one environmental agent at a time, only infrequently adjusting for the potential confounding effects of the others. In reality we are exposed to these air pollutants and weather variables simultaneously. Therefore without rigorous approaches to estimate the health effects associated with multiple exposures, the health burden will likely be underestimated. In addition to a rigorous and comprehensive quantification of these health effects, it is important to characterize susceptibility and identify modifying factors so the health consequences of multiple exposures can be prevented and reduced. While inherent characteristics, lifestyle, and contextual factors are hypothesized to either exacerbate or mitigate adverse health effects, very little is known regarding their potential interaction with multiple exposures. Specifically, very little is known regarding 1) which lifestyle factors (e.g. physical activity, diet, smoking) can mitigate or further exacerbate adverse effects of both air pollution and temperature; 2) which contextual measures (e.g. walkability, green space) can mitigate these risks; and 4) whether multiple exposures also affect survival after a non-fatal myocardial infarction (MI). Furthermore, no study has been able to consider the real-world situation of the simultaneous effects of multiple modifying factors. The goals of this proposal are to comprehensively address these gaps of knowledge. We have access to an unprecedented collection of five large US-based cohorts with a wealth of time-varying information on lifestyle factors, residential addresses, and medical record confirmed cases: the Nurses' Health Study (NHS), the Nurses' Health Study II (NHSII), the Health Professionals' Follow-up Study (HPFS), the whole cohort of Medicare enrollees (MC), and the Medicare Current Beneficiary Survey linked to Medicare Claims data (MC- MCBS). Our specific aims are to develop new methods to assess multiple exposures in the context of multiple confounding and effect modification; to assess the association between long-term exposure to multiple environmental agents (air pollution and weather) on risk of CVD, mortality, and survival after a non-fatal MI; and to characterize interactions between multiple environmental exposures, inherent characteristics, contextual and lifestyle factors.